1. Field of the Invention
The present invention relates to novel azole compounds, salts thereof, and uses of such an azole compound as a pharmaceutical product. The compounds of the present invention inhibit the physiological activity of lysophosphatidic acid (LPA), and therefore, are useful as agents for the prophylaxis or treatment of diseases in which inhibition of the physiological activity of LPA is useful for the prophylaxis or treatment thereof, such as diseases in which LDA receptor participates. More specifically, the compounds are useful as agents for the prophylaxis or treatment of fibrosis of organs (liver, kidney, lung, and the like), liver diseases (acute or chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and the like), cell proliferative disease (cancer (solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, and the like) and invasive metastasis of cancer cell, and the like), inflammatory disease (psoriasis, nephropathy, pneumonia and the like), gastrointestinal tract disease (irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), abnormal pancreatic secretion, and the like), renal disease, urinary tract-associated disease (benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, symptoms derived from diabetes, lower urinary tract disease (obstruction of lower urinary tract, and the like), inflammatory disease of lower urinary tract, dysuria, frequent urination, and the like), pancreas disease, abnormal angiogenesis-associated disease (arterial obstruction and the like), brain-associated disease (cerebral infarction, cerebral hemorrhage, and the like), peripheral neuropathy, and the like. Particularly, the present compounds are useful as agents for the prophylaxis or treatment of fibrosis of organs (liver, kidney, lung, and the like) or liver diseases.
2. Discussion of the Background
Lysophosphatidic acid (LPA) exists in a trace amount in living organisms, and is a lysophospholipid that shows various physiological activities. LPA is produced and released from various cells stimulated by a physiologically active substance (The Journal of Biological Chemistry, (US), 1995, vol. 270, pp. 12949-12952 and The Journal of Biological Chemistry, (US), 1992, vol. 267, pp. 10988-10993). Since it is present in a small amount in plasma and in an abundant amount in serum in living organisms, the major site (cell) of production is considered to be platelets (The Biochemical Journal, (UK), 1993, vol. 291, pp. 677-680). Thus, LPA concentration is considered to increase in the topical site of inflammation or hemorrhage. In fact, it has been reported that LPA concentration increases in human arteriosclerosis lesion and in brain spinal fluid in intracerebral hemorrhage model (Proceedings of the National Academy of Sciences USA, (US), 1999, vol. 96, pp. 6931-6936 and Journal of Neurochemistry, (UK), 1996, vol. 67, pp. 2300-2305). Moreover, activation of platelets has been reported in acute or chronic hepatitis patients (The Tokai Journal of Experimental and Clinical Medicine, (JP), 2002, vol. 27, pp. 101-106, Hepato-Gastroenterology, (GK), 2001, vol. 48, pp. 818-822, and Journal of Investigative Medicine, (US), 2001, vol. 49, pp. 407-412), and an increase in the LPA concentration at a blood or liver topical site is suggested in both acute and chronic hepatitis patients. In addition, there is a report on an increased LPA concentration in ascites of intraperitoneal disseminated ovarian cancer patients and in the blood of multiple myeloma patients (Gynecologic Oncology, (US), 1998, vol. 71, pp. 364-368 and Lipids, (US), 1999, vol. 34, pp. 17-21).
It is being elucidated that LPA functions as an intercellular messenger that extracellularly acts via a cell surface receptor. The genes of the receptor, G-protein-coupled receptor, EDG2 (endothelial differentiation gene 2) (a.k.a. lpA1 (Lysophophatidic acid receptor 1) or VZG-1) (Biochemical and Biophysical Research Communications, (US), 1997, vol. 231, pp. 619-622), EDG4 (a.k.a. lpA2 (lysophophatidic acid receptor 2)) and EDG7 (a.k.a. lpA3 (lysophophatidic acid receptor 3)) gene have been cloned to the present date (Molecular Pharmacology, (US), 2000, vol. 58, pp. 1188-1196), and they have been reported to be LPA specific receptors (FEBS Letters, (DE), 2000, vol. 478, pp. 159-165 and Prostaglandins & other Lipid Mediators (US), 2001, vol. 64, pp. 21-32).
As the physiological activity of LPA, for example, cell growth promoting action, enhancing action on chemotactic and infiltrating activities, platelet aggregation action, action of cell contraction and the like are known, and LPA is particularly useful for the organs shown below, particularly for the disease/symptoms in organ shown below.
LPA has been reported to promote growth of stellate cell in the liver (Biochemical and Biophysical Research Communications, (US), 2000, vol. 248, pp. 436-440). LPA has also been reported to cause contraction of cultured activated stellate cells (Biochemical and Biophysical Research Communications, (US), 2000, vol. 277, pp. 72-78). When the contracting function of stellate cells is promoted by liver injury, it is considered that hepatic sinusoid microcirculation is impaired, the blood stream into the liver is prevented, causing portal hypertension and further esophageal varices (Seminars in Liver Disease, (US), 2001, vol. 21, pp. 337-349 and Gut, (UK), 2002, vol. 50, pp. 571-581). LPA has also been reported to induce chemotaxis of stellate cells (Journal of Biomedical Science, (CH), 2003, vol. 10, pp. 352-358). On the other hand, LPA has been reported to inhibit the growth of parenchymal cells stimulated by HGF (hepatic growth factor) (Biochemical and Biophysical Research Communications, (US), 2000, vol. 248, pp. 436-440).
As one of the pharmacological activities induced by LPA, the contracting phenomenon of rat colon and guinea pig ileum has been reported (Journal of Pharmacy and Pharmacology, (UK), 1982, vol. 34, pp. 514-516 and Journal of Pharmacy and Pharmacology, (UK), 1991, vol. 43, pp. 774-778). In recent years, it has been shown that LPA promotes the contraction of ileum, as do acetylcholine and high K+ (Canadian journal of physiology and pharmacology, (CA), 2000, vol. 78, pp. 729-736).
With regard to pancreas, it has been described that LPA receptor antagonist has a decreasing action of pancreatic secretion (WO03/007991).
LPA has been reported to promote growth of vascular smooth muscle cell. WO01/060819 describes that the compound of Example 115 (methyl 3-([4-[4-([[1-(2-chlorophenyl)ethoxy]carbonyl]amino)-3-methyl-5-isoxazolyl]benzyl]-sulfanyl)propanoate) had a strong EDG2 antagonistic action and exhibited an improving action in peripheral circulation disorder model induced by lactic acid, which is an animal model of peripheral arterial obstruction.
There are reports that LPA has a contracting action on bladder smooth muscle cell isolated from bladder (The Journal of urology, (US), 1999, vol. 162, pp. 1779-1784), and promotes growth of prostate-derived epithelial cell (The Journal of urology, (US), 2000, vol. 163, pp. 1027-1032). In addition, WO02/062389 shows that LPA contracts the urinary tract and prostate in vitro and increases intraurethral pressure in vivo.
In addition, there is a report on the finding that, by LPA acting on a prostatic interstitial cell which expresses LPA receptor, the interstitial cell is grown and that the growth of the interstitial cell results in the progression of prostate hyperplasia (WO03/013605).
There are many reports on the involvement of LPA in the growth of cells responsible for the fibrosis of organs represented by fibroblasts in various organs. For example, smooth muscle cells (The American journal of physiology, (US), 1994, vol. 267, pp. C204-C210 and Atherosclerosis, (IE), 1997, vol. 130, pp. 121-131), renal mesangial cells (Clinical science, (UK), 1999, vol. 96, pp. 431-436), hepatic stellate cells (Biochemical and Biophysical Research Communications, (US), 2000, vol. 248, pp. 436-440), lung fibroblast (The Journal of Pharmacology and Experimental Therapeutics, (US), 2000, vol. 294, pp. 1076-1982), fibroblast (Naunyn-Schmiedeberg's archives of pharmacology, (DE), 1997, vol. 355, pp. 1-7) and the like can be mentioned. In general, when fibroblasts is proliferated, it is considered production of collagen is promoted, and also fibrosis of organs is considered to be promoted. Therefore, an LPA receptor antagonist is useful for the treatment or prophylaxis of fibrosis in various organs.
LPA promotes the growth of various cancer cells and is suggested to be related not only to diseases but also to infiltration and metastasis of cancer, because a promoting action of cancer cell infiltration and the like are observed (Biochemical and Biophysical Research Communications, (US), 1993, vol. 193, pp. 497-503).
LPA has been reported to promote the chemotactic ability of human monocytes (The Journal of Biological Chemistry, (US), 1995, vol. 270, pp. 25549-25556), and be involved in the growth and infiltration of T cells (Biochimica et Biophysica Acta, (DE), 2002, vol. 1582, pp. 168-174).
LPA has also been reported to cause neurite retraction and cell death in nerve cells, and is particularly suggested to be possibly involved in the injury of nerve cells during bleeding (Journal of Neurochemistry, (UK), 1993, vol. 61, pp. 340-343 and Journal of Neurochemistry, (UK), 1998, vol. 70, pp. 66-76).
A pharmaceutical agent that inhibits the above-mentioned physiological activities of LPA is considered to lead to the prophylaxis or treatment of fibrosis of organs (liver, kidney, lung, and the like), hepatic disease (acute or chronic hepatitis, liver fibrosis, liver cirrhosis, portal hypertension, regenerative failure, non-alcoholic steatohepatitis (NASH), liver hypofunction, hepatic blood flow disorder, and the like), cell proliferative disease (cancer (solid tumor, solid tumor metastasis, vascular fibroma, myeloma, multiple myeloma, Kaposi's sarcoma, leukemia, and the like) and invasive metastasis of cancer cell and the like), inflammatory disease (psoriasis, nephropathy, pneumonia, and the like), gastrointestinal tract disease (irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), abnormal pancreatic secretion, and the like), renal disease, urinary tract-associated disease (benign prostatic hyperplasia or symptoms associated with neuropathic bladder disease, spinal cord tumor, hernia of intervertebral disk, spinal canal stenosis, symptoms derived from diabetes, lower urinary tract disease (obstruction of lower urinary tract and the like), inflammatory disease of lower urinary tract, dysuria, frequent urination, and the like), pancreas disease, abnormal angiogenesis-associated disease (arterial obstruction and the like), brain-associated disease (cerebral infarction, cerebral hemorrhage, and the like), peripheral neuropathy, and the like.
As a compound having an azole skeleton as in the present invention, for example, WO01/060819 discloses isoxazole compounds and isothiazole compounds represented by the following formulas, which have an LPA receptor antagonistic action. However, WO01/060819 does not disclose compounds in which either R1 or R2 is a hydrogen atom.

In addition, a production method of the isothiazole compound of the following formula has been reported (Journal of Heterocyclic Chemistry, (US), 1977, vol. 14, pp. 725), but its biological activity has not been described at all.

In addition, several production methods of compounds having a diazole skeleton as in the present invention have been reported.
For example, EP-A-0120821 discloses oxadiazole compounds of the following formula as a herbicide, but the pharmaceutical use of such a compound is not described at all in EP-A-0120821.

As for such oxadiazole compounds, other references (Journal of the Chemical Society, Perkin Transactions 2, (UK), 1992, p. 1643, Farmaco, Edizione Scientifica, (IT), 1971, vol. 26, p. 241, etc.) report production methods thereof and the like, but do not describe their biological activities at all.
Furthermore, ZA-6800779 describes an oxadiazole compound of the following formula as one of the compounds having a central nervous system suppressing action, an anti-convulsion action, and a muscle relaxation action, but does not describe activity for any disease based on inhibition of the physiological activity of LPA as described in the present specification.

While a production method of N-oxy-oxadiazole compounds of the following formula has been reported (Journal of Heterocyclic Chemistry, (US), 1972, vol. 9, p. 837 and Journal of the Chemical Society, Perkin Transactions 2, (UK), 1973, p. 1613), its biological activity has not been described at all.

While a production method of thiadiazole compounds of the following formula has been reported (Journal of the Chemical Society), (UK), 1965, p. 5166), its biological activity has not been described at all.

While a production method of thiadiazole compounds of the following formula has been described (Chemical and Pharmaceutical Bulletin, (UK), 1981, vol. 29, p. 1743), its biological activity has not been described at all.
